Phase I trial of liposomal encapsulated doxorubicin (Myocet™; D-99) and weekly docetaxel in advanced breast cancer patients

Annals of Oncology 16: 1087– 1093, 2005 doi:10.1093/annonc/mdi209 Published online 22 April 2005

Original article

Phase I trial of liposomal encapsulated doxorubicin (Myocete; D-99) and weekly docetaxel in advanced breast cancer patients E. Mro´zek1, C. A. Rhoades1, J. Allen1, E. M. Hade2 & C. L. Shapiro1* 1 Division of Hematology and Oncology, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH; 2Comprehensive Cancer Center and Center for Biostatistics, Ohio State University, Columbus, OH, USA

Received 11 November 2004; revised 2 February 2005; accepted 3 February 2005

Introduction

Patients and methods

Docetaxel is the most active drug in metastatic breast cancer. Phase II and III clinical trials show that docetaxel alone, or in combination with other cytotoxic drugs, produces superior response rates, time to progression and, in some cases, provides a survival advantage over non-docetaxel containing regimens [1–4]. Doxorubicin is also one of most active drugs in breast cancer; however, its use is limited by cumulative cardiac toxicity [5 –7]. Non-pegylated liposome-encapsulated doxorubicin (Myocete; D-99) has similar anti-tumor activity to unencapsulated free doxorubicin, but causes less myocardial damage when administered as a single-agent or in combination with cyclophosphamide in metastatic breast cancer [8 – 11]. Based on the improved therapeutic index of D-99 relative to doxorubicin with respect to cumulative cardiac toxicity, we conducted a phase I study to determine the safety and to define the maximum tolerated dose (MTD) of D-99 and weekly docetaxel.

Patient eligibility

*Correspondence to: Dr C. L. Shapiro, B 405 Starling-Loving, 320 West 10th Avenue, Columbus, OH 43210, USA. Tel: +1-614-293-7530; Fax: +1-614-293-7529; E-mail: [email protected] q 2005 European Society for Medical Oncology

Patients age 18 years or older with histologically confirmed breast cancer, evidence of metastatic disease, and no prior chemotherapy for metastases were eligible. Patients who had received prior adjuvant taxanes and/or doxorubicin were eligible if the chemotherapy was completed more than 6 months prior to study entry, and the total cumulative dose of adjuvant _ 300 mg/M2. Hormone therapy in the adjuvant doxorubicin was limited to < or metastatic setting was permitted provided it was discontinued at least 3 weeks before study entry. Patients were required to have an Eastern Cooperative Oncology Group _ 2, and the following organ function: plate(ECOG) performance status < 3 _ 1500 cells/mm3; > _ lets 100 000 cells/mm ; absolute neutrophil count > _ 10 g/dl; serum creatinine <2.0 mg/dl; and pretreatment left hemoglobin > _ 50%. Due to the increased risk of ventricular ejection fraction (LVEF) > side-effects of docetaxel with impaired liver function, the total bilirubin was required to be less than or equal to the upper limit of normal (ULN); _ 2.5 times ULN if alkaline phosphatase was normal; or AST and ALT < _ 4 times ULN if AST and ALT were normal. alkaline phosphatase < Patients were excluded for a known hypersensitivity to taxanes, anthracyclines, polysorbate 80, eggs or eggs products; prior radiotherapy to mediastinal area or internal mammary lymph node exceeding 3500 cGy, or if they received radiation therapy to more than 25% of the bone marrow. Patients with untreated brain metastases were excluded. However, patients

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

Background: We conducted a phase I trial to determine the safety and maximum tolerated dose (MTD) of non-pegylated liposome-encapsulated doxorubicin (Myocete; D-99) administered with weekly docetaxel in metastatic breast cancer (MBC) patients. Patients and methods: Twenty-one patients with no prior chemotherapy for MBC received D-99 (60 or 50 mg/m2) intravenously (i.v.) on day 1 and escalating doses of docetaxel (25, 30 and 35 mg/m2) i.v. on days 1 and 8 in cohorts of three to six patients. Treatment cycles were repeated every 21 days for a maximum of six cycles. Results: The maximum tolerated dose (MTD) was 50 mg/m2 of D-99 in combination with 25 mg/m2 of weekly docetaxel. The most common grade 4 toxicity was neutropenia that occurred in 42 (41%) of treatment cycles, with 10 hospitalizations for febrile neutropenia. Serious protocol-defined cardiac events occurred in three (14%) patients, with two (10%; 95% confidence interval [CI] 1% to 30%) developing congestive heart failure (CHF) after a total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2. Conclusions: D-99 in combination with weekly docetaxel, at the doses and schedule as administered in this trial, is not recommended for phase II testing. Additional trials, using different doses and schedules, are required to evaluate the potential side-effects and efficacy of D-99 and docetaxel. Key words: liposome encapsulated doxorubicin, cardiotoxicity, breast cancer

1088 with previously treated brain metastases were eligible if they were stable for at least 3 months after surgery and/or radiation and were off steroids. Patients were not required to have bi-dimensionally measurable disease; if measurable disease was present, it was evaluated using standard response criteria (see below). The Institutional Review Board of the Ohio State University approved the study protocol, and written informed consent was obtained from each patient.

Treatment plan

Definition of dose limiting toxicity (DLT) and criteria for dose escalation and reductions Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. A dose limiting toxicity (DLT) occurring in cycle 1 was defined as follows: any grade 4 neutropenia lasting more than 7 days; febrile neutropenia; or any grade 4 non-hematologic toxicity, grade 3 mucositis or stomatitis lasting more than 3 days; or any other grade 3 non-hematologic toxicity that did not revert to grade 1 or less within 35 days. Cohorts of three to six patients were treated at a given dose level. There was no intra-patient dose escalation. Escalation to the next higher dose level took place only after all three patients had completed the first treatment cycle without evidence of DLT. If there was one DLT among the initial three patients, an additional three patients were treated at the same dose level. If two or less patients out of six experienced DLT, the dose was escalated to the next level. If more than two patients out of three experienced DLT in cycle 1, the dose was not escalated to the next level, and the MTD was defined as the next lower dose level. Patients were treated until disease progression, unacceptable toxicity, or a maximum of six cycles. There were no dose reductions for D-99. A docetaxel dose reduction of 5 mg/m2 was permitted for grade 4 neutropenic fever, grade 4 anemia or thrombocytopenia, serum bilirubin level 1.2  ULN, or grade 3 or 4 mucositis. Only one docetaxel dose reduction per patient was permitted. Dose delays of up to 14 days were permitted for _ grade 1, or grade 3 or 4 non-hematologic toxicity that did not revert to < _ 1000/mm3 and or platelet for an absolute neutrophil count (ANC) of < _ 100 000/mm3 on day 1 of a treatment cycle. Patients who did count of < _ grade 1 non-hematologic toxicity or failed to recover ANC not revert to < >1000/mm3 or platelet count >100 000/mm3 after 14 days were removed from the study.

Tumor evaluation and criteria for response All patients had imaging studies and/or physical examination measurements for assessment of tumor sites within 14 days before starting

Monitoring for cardiac toxicity All patients had an electrocardiogram (ECG) within 1 week of study entry, and a multiple-gated radionuclide angiography acquisition (MUGA) scan to quantitate LVEF within 4 weeks before treatment. Subsequent MUGA scans were required after patients received a total cumulative anthracycline dose (adjuvant doxorubicin and D-99) of 300 mg/m2, 400 mg/m2, and prior to each cycle after patients received a lifetime cumulative anthracycline dose of 500 mg/m2. Cardiac events were defined _ 20% if the final LVEF as follows: a decrease in the baseline LVEF of > _ 50%; a decrease in the baseline LVEF > _ 10% if the final LVEF was > <50%, or any clinical evidence of American Heart Association (AHA) Class III or IV congestive heart failure CHF. Patients were removed from study if they developed any cardiac event.

Statistical methods Median time to progression and median overall survival were estimated by the Kaplan–Meier method [12]. Confidence intervals for median time to progression and overall survival were calculated using the Brookmeyer–Crowley method [13]. Exact binomial confidence intervals are reported for all proportions.

Results Patients characteristics From September 1999 to April 2002, 21 patients were enrolled. Patient characteristics are described in Table 1. The median age was 54 years; 20 (95%) patients had an ECOG performance status of 0 or 1; 13 (62%) were postmenopausal; 14 (67%) were hormone receptor positive; and five (25%) were HER2/neu 3+ by immunohistochemistry. Fifteen (71%) patients received prior adjuvant chemotherapy with 12 (57%) receiving prior doxorubicin with a median dose of 240 mg/m2 (range 120–240 mg/m2). The median baseline LVEF was 64% (range 50% –74%). The skeleton was the most common site of metastases in 12 (57%) patients, followed by liver in eight (38%), and lung in seven (33%). Fourteen (67%) patients had two or more sites of metastases. Sixteen (76%) patients had bi-dimensionally measurable disease.

Results of dose escalation The median number of treatment cycles was 4 (range 1–6). Table 2 summarizes the dose escalations. The initial starting doses were 60 mg/m2 of D-99 in combination with 35 mg/m2 of docetaxel. Two of three patients treated with these doses

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

D-99 was provided by Elan Pharmaceuticals, Inc. (Princeton, NJ) in a three-vial set containing liposomes for injection 2 ml (100 mg/ml), doxorubicin hydrochloride powder (50 mg/vial) and buffer for injection 3 ml (sodium carbonate 17.6 mg/ml). The drug was prepared in the pharmacy according to standard manufacturers instructions just before administration. Docetaxel was obtained from commercial sources. D-99 at a dose of 50 –60 mg/m2 i.v. was administered on day 1 over 60 min by intravenous infusion. Docetaxel 25–35 mg/m2 i.v. was administered on days 1 and 8 over 60 min. The docetaxel infusion was started 30 min after completion of D-99 infusion. Patients received dexamethasone 8 mg orally every 12 h for three doses beginning 12 h prior to each docetaxel infusion. Treatment cycles were repeated every 21 days for a maximum of six cycles. The use of granulocyte colony stimulating factor (Neupogenw, G-CSF) or erythropoietin (Procritw) was at the discretion of the treating physician. Complete blood counts were obtained before and weekly, during each cycle.

treatment. The same imaging modalities were used for response evaluation after every two cycles, as well as at the time of discontinuation of study therapy. In those patients with measurable disease the definitions of response were as follows: complete response (CR) was the disappearance of all evidence of disease lasting at least 4 weeks; partial response (PR) _ 50% decrease in the sum of the products of the two longest was a > perpendicular diameters of all measured lesions lasting at least 4 weeks _ 50% decrease or < _ 25% and no new lesions; stable disease (SD) was a < increase in measurable disease and no new lesions; and progressive dis_ 25% increase in the product of the two longest perpenease (PD) was a > dicular diameters of any measurable disease lesion, or the appearance of a new lesion.

1089 Table 1. Patients demographics and baseline disease characteristics Clinical parameter

N

Median age (range)

54 (36–71)

Table 2. Dose escalation and treatment delivery %

ECOG performance status

D-99/DOC

N

No. cycle 1 DLT

Type DLT

60/35

3

Cycles 9

2

FN; G3 mucositis

50/25

6

32

0

None

0

8

38

50/30

7

36

2

FN; G3 mucositis

1

12

57

50/35

5

26

2

G3 mucositis

2

1

5

18

85

3

15

Premenopausal

8

38

Postmenopausal

13

62

14

67

ER/PR-negative

7

33

HER2 IHC 0–2+

15

71

HER2 IHC 3+

5

25

HER2 unknown

1

5

Adjuvant chemotherapy

15

71

Adjuvant doxorubicin

12

57

9

39

1

5

11

52

Race White African–American Menopausal status

ER or PR-positive

Prior therapy

Radiation therapy

Overall toxicity

Prior cumulative dose of doxorubicin <240 mg/m2 2

240 mg/m

Median LVEF (range)

docetaxel, and dose levels 2 and 3 were the same dose of D-99 in combination with 30 and 35 mg/m2 of docetaxel, respectively. The first three patients enrolled on dose levels 1 and 2 did not experience any DLT. However, two of five patients at dose level 3 experienced a DLT. An additional four patients were enrolled at dose level 2, but two of them experienced a DLT in cycle 1, and therefore the MTD was defined as 50 mg/m2 of D-99 in combination with 25 mg/m2 of docetaxel on days 1 and 8. At dose level 1, none of six patients experienced DLT.

64% (50%–79%)

Disease-free interval Overall

33 months (range 7–165 months)

Prior doxorubicin

25 months (range 8–110 months)

Of the 103 treatment cycles, in 20 (19%) the docetaxel doses were reduced, and in 20 (19%) doses were delayed. Table 3 describes hematologic toxicity. Grade 4 neutropenia occurred in 42 (41%) treatment cycles, with 10 (10%) hospitalizations for febrile neutropenia. After a documented episode of febrile neutropenia, G-CSF was started in the majority of patients. Only two (10%) patients required packed red blood cell (PRBC) transfusions for grade 3 anemia, and three (14%) patients received erythropoietin. Non-hematologic toxicity is described in Table 4. Twenty (19%) treatment cycles were Table 3. Hematologic toxicity in 103 treatment cycles

Site of metastatic disease Skeleton Liver

Overall (%)

Grade 3 (%) 23 (22)

12

57

Neutropenia

79 (77)

8

38

Neutropenic fever

10 (10) 78 (76)

Lung

7

33

Anemia

Lymph nodes

7

33

Thrombocytopenia

Malignant effusions

3

14

1

7

33

2

8

38

> _3

6

29

Number of metastatic sites

7 (7)

0

Grade 4 (%) 42 (41) 10 (10)

2 (2)

0

0

0

Table 4. Non-hematologic toxicity in 103 treatment cycles

ER, estrogen receptor; PR, progesterone receptor; IHC, immunohistochemical; LVEF, left ventricular ejection function.

Overall (%)

Grade 4 (%) 1 (1)

Nausea

26 (25)

2 (2)

Vomiting

19 (18)

2 (2)

1 (1)

Diarrhea

21 (20)

6 (6)

0

Stomatitis

40 (38)

Sensory neuropathy

experienced a DLT in cycle 1, and the third patient experienced a 27% reduction in LVEF after four cycles. Subsequently, drug doses were reduced such that dose level 1 was 50 mg/m2 of D-99 in combination with 25 mg/m2 of

Grade 3 (%)

Asthenia Peripheral edema Eye tearing

9 (9)

7 (7)

1 (1)

0

0

26 (25)

2 (2)

0

7 (7)

1 (1)

0

0

0

10 (10)

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

Receptor status

DOC, docetaxel; FN, febrile neutropenia; G3, grade 3; DLT, dose limiting toxicity.

1090 associated with either grade 3 or 4 gastrointestinal toxicities (nausea, vomiting, diarrhea and stomatitis). Severe (grade 3) asthenia was reported in only two (2%) treatment cycles, and there were no instances of palmar plantar erythrodysesthesia. Twenty (19%) treatment cycles were delayed mainly for grade 4 neutropenia and grades 3 or 4 mucositis. Other docetaxelspecific toxicities including asthenia, fluid retention, nail disorders, and eye tearing were virtually all grades 2 or less and did not result in treatment delays or cause patients to be removed from study.

Cardiac toxicity

Table 5. Cumulative anthracycline dose (adjuvant doxorubicin + D-99) and cardiac toxicity Dose (mg/m2)

n

<240

1

240–300

9

>300–400

4

>400–500

1

>500–600

6

Cardiac toxicitya n (%)

CHF n (%)

1 (5%)

a

2 (10%)

Defined as a decrease in the baseline left ventricular ejection fractipon _ 20% if the final LVEF was > _ 50%, or a decrease in the (LVEF) of > _ 10% if the final LVEF <50%. baseline LVEF >

Response and survival data

Figure 1. Left ventricular ejection fraction pre- and post-therapy.

Eight (38%) patients were removed from the study: four (19%) for PD, including one who expired from respiratory failure due to refractory progressive malignant effusions, and four (19%) for DLT. Sixteen patients had bidimensional measurable disease and were evaluable for response (Table 6). The overall response rate for all 21 patients was 29% (95% CI 11% to 52%), and 38% (95% CI 15% to 65%) among the patients with measurable disease. The time to progression (TTP) and overall survival in all patients was 8.8 months (95% CI 3.7 –12.4 months) and 22.2 months (95% CI 15.4 – 29.7 months), respectively.

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

The median total cumulative anthracycline dose (adjuvant doxorubicin + D-99) was 335 mg/m2 (range 240–540 mg/m2). Table 5 describes the total cumulative anthracycline dose and incidence of cardiac events. Six (29%) patients received a total cumulative anthracycline dose of 540 mg/m2, 14 (66%) received doses ranging from 250 to 480 mg/m2, one (5%) received 240 mg/m2. All 21 (100%) patients had pre- and 19 (90%) had post-therapy MUGA (Figure 1). The median LVEF before treatment was 64%, (range 50% –79%) and 1 month after treatment was 65% (range 51% –79%). For the 12 patients who had received doxorubicin in the adjuvant setting the median baseline LVEF was 64% (range 51% –74%), and 1 month after treatment, the median LVEF was 62% (range 29% –74%).

Three (14%; 95% CI 3% to 36%) patients had cardiac events that occurred either during or within 8 weeks of completing treatment. After a cumulative anthracycline dose of 240 mg/m2, patient 1 developed a 27% decrease in LVEF from a pre-study baseline of 79% to 52% after four cycles of D-99. She was asymptomatic but was removed from study per protocol guidelines. Two (10%; 95% CI 1% to 30%) patients developed grade 3 CHF shortly after completion of study treatment. Both patients received adjuvant doxorubicin dose of 240 mg/m2, and total cumulative anthracycline dose (adjuvant doxorubicin + D-99) of 540 mg/m2. Patient 2 presented with acute CHF about 7 weeks after completing all six treatment cycles at the dose level of 50/30. Her pre- and post-treatment LVEF were 59% and 51%, respectively, but at the time she presented with symptomatic CHF, the LVEF was 29%. This patient responded to medical treatment for CHF and subsequent LVEF improved to 62%. Patient 3 developed CHF about 6 weeks after completing six cycles of study treatment at the dose level of 50/25. She also had a history of left-sided postmastectomy chest wall irradiation after her adjuvant chemotherapy. Her pre- and post-study LVEF were 57% and 52%, respectively, but at the time of symptoms of CHF, the LVEF was 30%. In addition, there was evidence of thrombus in the left ventricle and small pericardial effusion. Patient 3 was treated with anticoagulation and was discharged from the hospital on medication for CHF. Ten days after discharge she presented to an emergency room with acute respiratory failure and died. There was no post-mortem examination. Patients 2 and 3 did not receive chemotherapy, hormonal treatment, or any other potential cardiotoxic drug after completing study treatment and before presenting with CHF. In addition, both patients had no evidence of acute myocardial injury by serial enzymes or electrocardiographic changes, or pulmonary embolus at the time of presentation of CHF. Two additional patients developed cardiac events 4 and 9 months after completion of study therapy, but only after starting another phase I clinical trial of trastuzumab (Herceptinw) and interleukin 12 (IL-12).

1091

Best response

Measurable n = 16 (%)

Non-measurable n = 5 (%)

CR

0

0

PR

6 (29)

0

SD

5 (24)

5 (24)

PD

4 (19)

0

a

DLT in cycle 1

1 (5)

Overall response

29% (95% CI 11% to 52%)

TTPb (months)

8.8 (range 1.4 –17.9; 95% CI 3.7 –12.4)

OSb (months)

22.2 (range 1.4 –50.2; 95% CI 15.4–29.7)

a

Removed from study after one cycle. Median; from the time of first treatment on trial. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; DLT, dose-limiting toxicity; TTP, time to progression; OS, overall survival. b

Discussion Dose escalation of docetaxel in combination with D-99 was limited by grade 3 and 4 mucositis and febrile neutropenia. Grade 4 neutropenia was the most frequent adverse event occurring in 41% of treatment cycles. In addition, three (14%) patients had a protocol-defined cardiotoxicity, including two (10%) with CHF after they received a total cumulative anthracycline dose of 540 mg/m2. Serial measurements of resting LVEF by radionuclide ventriculography in the patients who

Table 7. Clinical trials of docetaxel and conventional doxorubicin or liposome-encapsulated doxorubicins Trial

n

Phase

Prior chemoa/Adj. Dox

Regimen Dox/DOC (mg/m2)

CHF (%)

ORR (%)

TTP (months)

OS (months)

With D-99 Current

21

I

No/Yes

50/25c

10

29

9

22

Marty [15]

15

I

No/Yes

60/75

0

33

NA

NA

Sparano [16]

54

II

No/No

60/60

6

57

8

28

Cresta [17]

41

II

No/Yes

60/60

10

63

8

34

With doxorubicin

Nabholtz [18]

214

III

No/No

50/75

3

59

5

23

Baltali [19]

43

II

No/No

60/80

0

79

8

NA

Misset [20]

42

I

No/Yes

40–60/50–85

0

71

10

NA

With Doxil (Caelyxe)

a

Sparano [21]

31

I

Yes/Yes

30, 40, 45/60,75

0

52

8

18

Alexopoulos [22]

44

II

No/Yes

30/75

0

64

NA

NA

b

Gasparini [23]

20

II

No/NA

35/35+35

Chodkiewicz [24]

18

I

Yes/NA

30/80

0

75

6

NA

NA

43

NA

NA

Prior systemic chemotherapy for metastatic disease. Doxil given on days 2 and 9. c D-99 given on days 1 and 8. Adj, adjuvant; CHF, congestive heart failure; DOC, docetaxel; Dox, doxorubicin; TTP, time to progression; OS, overall survival. b

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

developed CHF failed to predict development of doxorubicin cardiomyopathy. This is consistent with other studies that show the sensitivity of resting LVEF to predict subsequent CHF is only about 50% [14]. This study did not use exercise radionuclide ventriculography, which may increase the sensitivity of detecting subclinical myocardial damage when the resting LVEF is in the normal range [6]. Previous studies of D-99 as a single agent or in combination with cyclophosphamide showed 0%–2% incidence of CHF. In a phase III trial comparing D-99 with conventional doxorubicin, only two out of 108 (2%) patients treated with 75 mg/m2 D-99 developed CHF [10]. These two patients received a total cumulative anthracycline (adjuvant doxorubicin + D-99) dose of 785 and 1100 mg/m2, respectively. Similarly, in a phase III trial comparing D-99 and cyclophosphamide (MC) with conventional doxorubicin and cyclophosphamide (AC), none of the 142 patients treated with MC developed CHF after receiving a median cumulative anthracycline dose of 360 mg/m2 (range 60 –2220 mg/m2) [11]. In the only other phase I study of D-99 (60–75 mg/m2) and docetaxel (75– 85 mg/m2) given every 3 weeks, there were no cases of CHF or decline in LVEF sufficient to remove the patients from the study [15]. The incidence of CHF ranges from 0% to 10% in clinical trials of conventional doxorubicin combined with docetaxel (Table 7) [16 –20]. In contrast, no CHF was observed using pegylated liposomal doxorubicin (Doxilw) in combination with docetaxel [21–24]. There are several possible explanations for the relatively high incidence of CHF observed in this study. First, because of the small trial population, the true proportion of CHF is as low as 1% or as high as 30%. It is also possible that patient 3 developed CHF because she had

Table 6. Response rates, time to progression and overall survival

1092

Acknowledgements This paper was presented in part at the American Society of Clinical Oncology Meeting in 2002. Elan Pharmaceuticals and Aventis Pharmaceuticals supported this trial.

References 1. Valero V, Holmes FA, Walters RS et al. Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer. J Clin Oncol 1995; 13: 2886–2894. 2. Trudeau ME, Eisenhauer EA, Higgins BP et al. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996; 14: 422 –428.

3. O’ Brien ME, Leonard RC, Barrett-Lee PJ et al. Docetaxel in the community setting: an analysis of 377 breast cancer patients treated with docetaxel (Taxotere) in the UK. UK Study Group. Ann Oncol 1999; 10: 205–210. 4. Nabholtz JM, Senn HJ, Bezwoda WR et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracyclinecontaining chemotherapy. J Clin Oncol 1999; 17: 1413–1424. 5. A’Hern RP, Smith IE, Ebbs SR. Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper-type regimens. Br J Cancer 1993; 67: 801–805. 6. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med 1996; 125: 47–58. 7. Singal P, Iliskovic N. Doxorubicin-induced cardiomyopathy. New Engl J Med 1998; 13: 900–905. 8. Cowens JW, Creaven PJ, Greco WR et al. Initial clinical (phase I) trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res 1993; 53: 2796– 2802. 9. Valero V, Buzdar A, Theriault R et al. Phase II trial of liposomeencapsulated doxorubicin, cyclophosphamide and fluorouracil as firstline therapy in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 1425–1434. 10. Harris L, Batist G, Belt R et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast cancer. Cancer 2002; 94: 25–36. 11. Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and preserved antitumor activity of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized multicenter trial of metastatic breast cancer. J Clin Oncol 2001; 19: 1444– 1454. 12. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457 –481. 13. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. Biometrics 1982; 38: 29–41. 14. McKillop JH, Bristow MR, Goris ML, Billingham ME, Bockemuehl K. Sensitivity and specificity of radionuclide ejection fractions in doxorubicin cardiotoxicity. Am Heart J 1983; 106: 1048–1056. 15. Marty M, Laurence V, Cottu P et al. A phase I dose escalation study of non-pegylated liposomal doxorubicin (M) and docetaxel (D) in patients with previously untreated advanced breast cancer. Ann Oncol 2002; 13 (Suppl 5): 55. 16. Sparano JA, O’Neill A, Schaefer PL, Falkson CI, Wood WC. Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer. Eastern Cooperative Oncology Group Study E1196. J Clin Oncol 2000; 18: 2369– 2377. 17. Cresta S, Grasselli G, Mansutti M et al. A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer. Ann Oncol 2004; 15: 433 –439. 18. Nabholtz JM, Falkson C, Campos D et al. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as firstline chemotherapy for metastatic breast cancer: Results of randomized multicenter, phase III trial. J Clin Oncol 2003; 21: 968–975. 19. Baltali E, Ozisik Y, Guler N, Firat D, Altundag K. Combination of docetaxel and doxorubicin as first-line chemotherapy in metastatic breast cancer. Tumori 2001; 87: 18–19. 20. Misset JL, Dieras V, Gruia G et al. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 1999; 10: 553 –560.

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015

received postmastectomy chest wall radiation in addition to a total cumulative dose of doxorubicin (adjuvant doxorubicin plus D-99) of 540 mg/m2. In a prospective randomized adjuvant trial, patients with localized breast cancer received 225 or 450 mg/m2 adjuvant doxorubicin, and a portion of them received postmastectomy radiation [25]. Acute and long-term cardiac events, including CHF and myocardial infarction, were the primary end points of the study. Whereas no increase cardiac events occurred in patients receiving 225 mg/m2 of doxorubicin along with any dose-volume of chest wall radiation, patients who received 450 mg/m2 and moderate or high dose-volumes of chest wall radiation were at significantly higher risks of acute and long-term cardiac events [25]. Another possibility is that weekly administration of docetaxel had a significant effect on pharmacokinetic (PK) and toxicity profile of D-99. Unlike paclitaxel, there is little or no evidence that docetaxel affects the PK of doxorubicin or pegylated liposomal doxorubicin [26,27]. To our knowledge, however, there are no PK studies of docetaxel and D-99 reported. Our intention was to collect PK samples of D-99 on a subset of patients to evaluate peak plasma levels and clearance of drug. Unfortunately, blood samples were collected from only one patient after the study sponsor withdrew support for PK analysis due to methodological problems with D-99 assay. The primary objective of this phase I trial was not to define the response rate for this combination. However, the overall response rate of 29%, and 38% for patients who had measurable disease, was below the response rates observed by other investigators using combinations of conventional or liposomal doxorubicin with docetaxel in similar MBC patients (Table 7). Likewise, the low response rate in this trial is consistent with the 33% response rate in the only other phase I trial of D-99 and docetaxel [15]. D-99 combined with weekly docetaxel as administered in this phase I trial did not show improved cardiac safety and had low antitumor activity in MBC patients without prior chemotherapy for metastases. Phase II testing of this combination is not recommended. Additional trials, using different doses and schedules, are required to evaluate the potential cardiac, as well as other, side-effects and efficacy of D-99 and docetaxel.

1093 21. Sparano JA, Malik U, Rajdev L, Sarta C, Hopkins U, Wolff AC. Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer. J Clin Oncol 2001; 19: 3117–3125. 22. Alexopoulos A, Karamouzis MV, Stavrinides H et al. Phase II study of pegylated liposomal doxorubicin (Caelyx) and docetaxel as firstline treatment in metastatic breast cancer. Ann Oncol 2004; 15: 891 –895. 23. Gasparini G, Gattuso D, Morabito A et al. Liposomal doxorubicin and docetaxel as first line therapy in patients with metastatic breast cancer. Ann Oncol 2002; 13 (Suppl 5): 55. 24. Chodkiewicz C, Wasserheith C, Downey A et al. Doxil (D) and Docetaxel (Taxotere, T): pharmacokinetic (PK) results at the

recommended phase II dose (RPTD). Proc Am Soc Clin Oncol 2000; 19: 212a. 25. Shapiro CL, Hardenbergh-Harrigan P, Gelman R et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 1998; 16: 3493–3501. 26. Holmes FA, Rowinsky EK. Pharmacokinetic profiles of doxorubicin in combination with taxanes. Semin Oncol 2001; 28: 8–14. 27. Briasoulis E, Karavaslis V, Tzamakou E et al. Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on co-adminstration with paclitaxel or docetaxel. Cancer Chemother Pharmacol 2004; 53: 452–457.

Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF PITTSBURGH on March 14, 2015